ERGIC-53 transports certain subsets of newly synthesized secretory proteins and membrane proteins from the endoplasmic reticulum to the Golgi apparatus. Despite numerous structural and functional studies since its identification, the overall architecture and mechanism of action of ERGIC-53 remain unclear. Here we present cryo-EM structures of full-length ERGIC-53 in complex with its functional partner MCFD2. These structures reveal that ERGIC-53 exists as a homotetramer, not a homohexamer as previously suggested, and comprises a four-leaf clover-like head and a long stalk composed of three sets of four-helix coiled-coil followed by a transmembrane domain. 3D variability analysis visualizes the flexible motion of the long stalk and local plasticity of the head region. Notably, MCFD2 is shown to possess a Zn²⁺-binding site in its N-terminal lid, which appears to modulate cargo binding. Altogether, distinct mechanisms of cargo capture and release by ERGIC- 53 via the stalk bending and metal binding are proposed.

ERGIC-53 将新合成的分泌蛋白和膜蛋白的某些子集从内质网转运到高尔基体。尽管自鉴定以来进行了大量的结构和功能研究，但 ERGIC-53 的整体结构和作用机制仍不清楚。在这里，我们展示了全长 ERGIC-53 与其功能伙伴 MCFD2 复合的冷冻电镜结构。这些结构表明ERGIC-53以同源四聚体的形式存在，而不是之前提出的同源六聚体，并包含一个四叶草状的头部和一个由三组四螺旋卷曲螺旋组成的长柄，后面是一个跨膜结构域。 3D 变异性分析可视化长柄的灵活运动和头部区域的局部可塑性。值得注意的是，MCFD2 在其 N 端盖中具有 Zn ²⁺结合位点，这似乎可以调节货物结合。总而言之，提出了 ERGIC-53 通过茎弯曲和金属结合捕获和释放货物的不同机制。